2-27498276-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_001486.4(GCKR):c.307G>A(p.Val103Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00095 in 1,613,632 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0017 ( 2 hom., cov: 32)

Exomes 𝑓: 0.00088 ( 8 hom. )

Consequence

GCKR
NM_001486.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:2B:1

Conservation

PhyloP100: 3.05

Publications

17 publications found

Variant links:

Genes affected

GCKR (HGNC:4196): (glucokinase regulator) This gene encodes a protein belonging to the GCKR subfamily of the SIS (Sugar ISomerase) family of proteins. The gene product is a regulatory protein that inhibits glucokinase in liver and pancreatic islet cells by binding non-covalently to form an inactive complex with the enzyme. This gene is considered a susceptibility gene candidate for a form of maturity-onset diabetes of the young (MODY). [provided by RefSeq, Jul 2008]

GCKR links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.013950884).

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GCKR	NM_001486.4 link	c.307G>A	p.Val103Met	missense_variant	Exon 4 of 19	ENST00000264717.7	NP_001477.2	Q14397A0A0C4DFN2
GCKR	XM_011532763.1 link	c.307G>A	p.Val103Met	missense_variant	Exon 4 of 13		XP_011531065.1
GCKR	XR_001738699.1 link	n.373G>A		non_coding_transcript_exon_variant	Exon 4 of 13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
GCKR	ENST00000264717.7 link	c.307G>A	p.Val103Met	missense_variant	Exon 4 of 19	1	NM_001486.4	ENSP00000264717.2	A0A0C4DFN2
GCKR	ENST00000472290.1 link	n.329G>A		non_coding_transcript_exon_variant	Exon 4 of 11	1
GCKR	ENST00000453813.1 link	c.223G>A	p.Val75Met	missense_variant	Exon 3 of 8	3		ENSP00000399463.1	H7C1B4
GCKR	ENST00000417872.5 link	n.364G>A		non_coding_transcript_exon_variant	Exon 4 of 7	4

Frequencies

GnomAD3 genomes

AF:

0.00166

AC:

253

AN:

152164

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000338

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0119

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00926

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00287

GnomAD2 exomes

AF:

0.00268

AC:

674

AN:

251402

AF XY:

0.00213

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.0144

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00848

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00212

GnomAD4 exome

AF:

0.000876

AC:

1280

AN:

1461350

Hom.:

Cov.:

AF XY:

0.000798

AC XY:

580

AN XY:

727000

show subpopulations

African (AFR)

AF:

0.000209

AC:

AN:

33472

American (AMR)

AF:

0.0147

AC:

657

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.0134

AC:

530

AN:

39694

South Asian (SAS)

AF:

0.000128

AC:

AN:

86230

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000153

AC:

AN:

1111544

Other (OTH)

AF:

0.000961

AC:

AN:

60376

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

135

202

270

337

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00166

AC:

253

AN:

152282

Hom.:

Cov.:

AF XY:

0.00185

AC XY:

138

AN XY:

74460

show subpopulations

African (AFR)

AF:

0.000337

AC:

AN:

41566

American (AMR)

AF:

0.0118

AC:

181

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00928

AC:

AN:

5174

South Asian (SAS)

AF:

0.000208

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

68030

Other (OTH)

AF:

0.00284

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000706

Hom.:

Bravo

AF:

0.00283

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00228

AC:

277

Asia WGS

AF:

0.00346

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:2Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

FASTING PLASMA GLUCOSE LEVEL QUANTITATIVE TRAIT LOCUS 5

Pathogenic:1

Mar 18, 2016

Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:reference population

- -

not specified

Uncertain:1

May 04, 2022

Mendelics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hypertriglyceridemia

Uncertain:1

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:research

The heterozygous p.Val103Met variant in GCKR has been identified in 2 individuals with hypertriglyceridaemia (PMID: 22182842), but has also been identified in >1% of Latino chromosomes and 3 homozygotes by ExAC (http://gnomad.broadinstitute.org/). In vitro functional studies provide some evidence that the p.Val103Met variant may impact protein function (PMID: 22182842). However, these types of assays may not accurately represent biological function. In summary, the clinical significance of this variant is uncertain. -

not provided

Benign:1

Dec 21, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.51

BayesDel_addAF

Benign

-0.097

BayesDel_noAF

Uncertain

0.10

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.45

T;D

Eigen

Uncertain

0.41

Eigen_PC

Uncertain

0.30

FATHMM_MKL

Uncertain

0.85

LIST_S2

Benign

0.85

D;D

MetaRNN

Benign

0.014

T;T

MetaSVM

Uncertain

0.13

PhyloP100

3.0

PrimateAI

Uncertain

0.58

PROVEAN

Uncertain

-2.5

N;D

REVEL

Pathogenic

0.69

Sift

Uncertain

0.0040

D;D

Sift4G

Benign

0.065

T;T

Vest4

0.82

MVP

0.87

MPC

0.36

ClinPred

0.83

GERP RS

2.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

gMVP

0.54

Mutation Taster

=70/30

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over